Immune function declines with age, resulting in increased susceptibility of aged individuals to infection and impaired responses to vaccines. A key focus of the current proposal is to use a well-characterized mouse model of influenza virus infection to determine mechanisms underlying the decreased ability of aged individuals to respond to and develop memory to new infections and vaccination. These studies are essential in order to develop strategies for overcoming these defects. The ability to generate T cell responses to newly encountered antigens and to respond to vaccination is dependent on the maintenance of a diverse repertoire of T cells. We have previously shown that there is an age-associated reduction in repertoire diversity among CD8 T cells, which has profound consequences for primary and protective immunity to influenza virus. Because of reduced numbers and diversity of naive T cells in aged individuals, we hypothesize that aging results in a greater contribution of fortuitously cross-reactive memory cells to the response to new infections, and that this will lead to stochastic responses, often of lower avidity, and perhaps detrimental or pathological. In support of this, we have preliminary data showing that fortuitously cross-reactive memory cells from influenza-naive aged mice can respond to influenza virus epitopes, and in Aim 1 we will determine the contribution of cross reactive memory to the response to new infections, and assess the implications for cellular immunity. Two additional well-characterized defects associated with aging are that CD4 T cells are functionally impaired and that poor CD8 T cell memory is generated. However, the contribution of aged CD4 T cells to the development of defective CD8 memory is an understudied area in aging research, and will be examined in Aim 2 of the proposal. Taken together, these studies will address mechanisms underlying the age-associated decline in cellular immunity which is essential for the goal of designing better therapies and vaccines for elderly humans. PUBLIC HEALTH RELEVANCE: The ability to respond to infection or vaccination decreases dramatically with age. Elderly individuals are significantly more susceptible to infections than the young, but, unfortunately, the elderly are also more difficult to vaccinate. Therefore, it is essential that we understand the defects in immunity of the aged so that we can develop vaccine strategies that can overcome these defects. The studies proposed will use a mouse model to determine the mechanisms underlying decreased immunity of the elderly, an essential first step in the design of better vaccines.